Indicators of sorafenib efficacy in patients with advanced hepatocellular carcinoma.

AIM: To determine significant indicators for the efficacy of sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 46 patients with Barcelona Clinic Liver Cancer stage C who received sorafenib for more than 30 d at the Iizuka Hospital from June 2009 to December 2012 were enrolled in this study. Multivariate and univariate analyses were performed to evaluate the associations of hepatic function according to Child-Pugh grade, location and size of the largest tumor and adverse events of sorafenib treatment, such as hand-foot syndrome (HFS), hypertension, diarrhea, and alopecia, with the efficacy of treatment, as measured by overall survival (OS) and time to progression (TTP). RESULTS: Patients included 39 men and 7 women whose ages ranged from 48 to 85 years (70.6 ± 9.6 years). HCC was classified according to etiology as follows: hepatitis C virus (n = 26), hepatitis B virus (n = 9), and other (n = 11). Liver function in patients was categorized as Child-Pugh grade A (n = 30) or B (n = 16). Tumors were categorized by size [< 5 cm (n = 33) or >5 cm (n = 13)] and the location of the largest tumor was used to categorize patients with intrahepatic (n = 28) or extrahepatic (n = 18) HCC. HFS, hypertension, diarrhea, and alopecia were present in 22 (47.8%), 19 (41.3%), 15 (32.6%) and 7 patients (15.2%), respectively. The median OS of all patients was 373 d and the median TTP was 112 d. The etiology of HCC did not correlate with the median OS and TPP. The median OS of patients with tumors < 5 cm was significantly longer than those with larger tumors (496 vs 245 d; HR = 0.19, 95%CI: 0.07-0.48; P < 0.01). According to the results of a multivariate analysis, the size of the largest tumor affected OS (HR = 0.22, 95%CI: 0.08-0.59; P < 0.01). The median TTP was significantly longer in patients with extrahepatic compared to intrahepatic major HCC (224 vs 98 d; HR = 0.32; 95%CI: 0.14-0.67; P < 0.01). The median TTP of patients with HFS was significantly longer than those without it (195 d vs 83 d; HR = 0.41, 95%CI: 0.20-0.82; P < 0.05), and the median TTP was significantly longer in patients with hypertension (195 d vs 84 d; HR = 0.43, 95%CI: 0.21-0.84; P < 0.05). According to the results of the multivariate analysis, extrahepatic major HCC (HR = 0.36, P < 0.01) and HFS (HR = 0.44, P < 0.05) prolonged TTP. CONCLUSION: Extrahepatic major HCC and HFS are associated with prolonged TTP and are useful indicators for judging the efficacy of sorafenib treatment.

Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease.

AIM: Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction and its incidence has increased markedly. However, the mechanisms involved in the pathogenesis of NAFLD in humans have not been thoroughly investigated. Sterol regulatory element binding protein (SREBP)-1c and carbohydrate responsive element binding protein (ChREBP) are transcriptional factors that regulate the expression of lipogenic genes, including acetyl-CoA carboxylases (ACCs) and fatty acid synthase (FAS). SREBP-1c and ChREBP are transactivated by liver X receptor (LXR), a nuclear receptor that regulates the metabolism of cholesterol and fatty acids. To understand the mechanisms involved in the pathogenesis of NAFLD, we investigated the transcriptional factors and lipogenic genes activated in the liver with NAFLD. METHODS: Real-time PCR was carried out on liver biopsy samples from 20 NAFLD patients. The target genes studied were: ACC1, FAS, SREBP-1c, ChREBP, AMP-activated protein kinase (AMPK), and LXRalpha. RESULTS: LXRalpha, SREBP-1c, ACC1, and FAS were upregulated in NAFLD patients. Expression levels of LXR were four times greater than those of the controls and correlated significantly with SREBP-1c, but not with ChREBP, levels. CONCLUSIONS: These findings suggest that LXR acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in NAFLD.

Investigation of hyperuricemia during pegylated-interferon-alpha2b plus ribavirin combination therapy in patients with chronic hepatitis C.

OBJECTIVE: Hyperuricemia has been reported as being an adverse effect of pegylated-interferon-alpha2b (Peg-IFNalpha2b) and ribavirin combination therapy for chronic hepatitis C and hyperuricemic changes occur in some patients during the therapy. However, detailed investigation of the elevation of uric acid has not been carried out previously. The incidence and mechanism of hyperuricemia were investigated in this study. METHODS: The data of 50 patients with chronic hepatitis C who had been treated with Peg-IFNalpha2b and ribavirin combination therapy or pegylated-interferon-alpha2a monotherapy for more than 24 weeks were analyzed. The effects of these treatments were evaluated clinically by the serum uric acid level and its urinary excretion rates. RESULTS: In patients with pegylated-interferon-alpha2a monotherapy, no significant elevation was shown either in serum uric acid concentrations or excretion rates. On the other hand, serum uric acid concentrations were significantly elevated during the combination therapy, reaching > or =7.0 mg/L in men and > or =6.5 mg/L in women in 15% of patients. The urinary uric acid excretion rate was also elevated significantly. CONCLUSION: Peg-IFNalpha2b plus ribavirin combination therapy induced an elevation of uric acid concentration, although the elevated levels were still within normal limit in many cases. It may be that ribavirin plays a leading role in its elevation and other factors may also be involved.

[Frequency of gastroesophageal reflux disease (GERD) as a complication in patients with chronic liver diseases: estimation of frequency scale for the system of GERD].

Recently, a questionnaire, Frequency Scale for the System of GERD (FSSG), has been estimated to be clinically useful for the initial diagnosis of gastroesophageal reflux disease (GERD). We investigated the frequency of GERD as a complication in patients with chronic liver diseases by using the questionnaire, FSSG. As a result, it may be considered that, as a complication of chronic liver disease, GERD exists in about 20% of patients and mainly belongs to a dyskinetic type.